Dynamic tailoring of treatment durations improves efficiency of hepatitis C treatment with pegylated interferon and ribavirin.

The treatment durations for hepatitis C are guided by the analysis of hepatitis C virus (HCV) RNA in blood at certain time points. This multicentre, randomized open label trial evaluated the utility and performance of individualized treatment durations guided by viral decline rates in 103 patients with HCV genotype 1 infection. Pegylated interferon 2a and ribavirin were given as standard of care (SOC) for 24, 48 or 72 weeks or as dynamic treatment (DT) for 24-72 weeks. The DT duration was based on the time point when log HCV RNA would reach 0 log copies/mL, as estimated by the second-phase decline. The rate of sustained virologic response was 63% for SOC and 54% for DT, but this difference was not significant in multiple regression analysis taking predictive factors such as interleukin-28B genotypes, age and baseline viremia into account (P = 0.45). The mean required treatment time per cured patient was 51 weeks for DT as compared with 58 weeks for SOC (P = 0.22) when given per protocol (n = 95) and was significantly shorter (42 vs 51 weeks) among patients who achieved undetectable HCV RNA (P = 0.01). We conclude that DT was feasible and increased efficiency. The estimated time point for 0 log viral copies/mL is a new and quantitative response variable, which may be used as a complement to the qualitative variable rapid virologic response. The outcome parameter treatment weeks per cured patient could become a useful tool for comparing treatment efficiency also in the era of directly acting antivirals.

IL28B polymorphisms determine early viral kinetics and treatment outcome in patients receiving peginterferon/ribavirin for chronic hepatitis C genotype 1.

Single nucleotide polymorphisms (SNPs) upstream of IL28B predict the outcome of treatment in chronic hepatitis C virus (HCV) infection, but their impact on viral kinetics and relation to other predictors are not well known. Here, two SNPs, rs12979860 and rs8099917, were analysed and related to early viral kinetics during treatment in 110 patients with HCV genotype 1 infection. The reduction of HCV RNA after 7 days of therapy was more pronounced (P < 0.0001) in patients with CC(rs12979860) or TT(rs8099917) than in patients carrying TT(rs12979860) or GG(rs8099917), respectively. The two SNPs were in linkage disequilibrium (d' = 1, r2 = 0.44), but CC(rs12979860) was less common (43% vs. 71%) than TT(rs8099917). Patients carrying both CC(rs12979860) and TT(rs8099917) genotypes achieved lower levels of HCV RNA at week 4 than those with CT or TT at rs12979860 and TT(rs8099917) (P = 0.0004). The viral elimination was significantly influenced by rs12979860 independently of baseline viral load, age or fibrosis. This translated into high rates of sustained viral response (SVR) among patients carrying CC(rs12979860) despite the presence of high viral load at baseline (SVR 74%), high age (SVR 79%) or severe liver fibrosis (SVR 83%). We conclude that the IL28B variability influences the antiviral efficiency of interferon/ribavirin therapy and has a strong impact on SVR, independently of traditional response predictors. A combined assessment of these SNPs in conjunction with other response predictors may better predict outcome in difficult-to-treat patients.

Hepatitis C treatment response kinetics and impact of baseline predictors.

The optimal duration of treatment for hepatitis C virus (HCV) infections is highly variable but critical for achieving cure (sustained virological response, SVR). We prospectively investigated the impact of age, fibrosis, baseline viraemia and genotype on the early viral kinetics and treatment outcome. Patients treated with peginterferon alfa-2a and ribavirin in standard dosing were included: 49 with genotype 1 treated for 48weeks and 139 with genotype 2 or 3 treated for 24weeks. The reduced SVR rates in patients older than 45years, with severe liver fibrosis or pretreatment viraemia above 400,000IU/mL were strongly associated with slower second phase declines of HCV RNA. Genotype 2/3 infections responded more rapidly than genotype 1, reaching week 4 negativity (RVR) in 59%vs 22%. We conclude that baseline response predictors such as age, fibrosis and viral load were well reflected by the early viral kinetics as assessed by repeated HCV RNA quantifications. The kinetic patterns and the high relapse rate in genotype 2/3 patients without RVR suggest that this group might benefit from treatment durations longer than 24weeks.

Moderate alcohol intake increases fibrosis progression in untreated patients with hepatitis C virus infection.

Although excessive alcohol consumption in combination with hepatitis C virus (HCV) infection is known to increase the risk of liver cirrhosis, the effect of moderate alcohol intake remains to be elucidated. The aim of this study was to evaluate the effect of moderate alcohol consumption on fibrosis progression in HCV infection. A group of 78 patients with HCV infection and moderate alcohol consumption were analysed retrospectively. All patients had undergone two liver biopsies, with a median time between biopsies of 6.3 years, and had not received any antiviral therapy. Their lifetime drinking history was recorded. All patients except one had daily alcohol consumption below 40 g of ethanol (median 4.8 g/day, interquartile range 1.1-11.6 g/day) during the period between the biopsies. The patients whose liver fibrosis had deteriorated had a higher total alcohol consumption and higher drinking frequency between the biopsies. The degree of fibrosis progression was greater in patients with a total alcohol intake and drinking frequency above the median level for the group. A multiple logistic regression analysis showed that drinking frequency and time between biopsies were independently associated with fibrosis progression. Hence, even moderate alcohol intake seems to increase fibrosis progression in HCV-infected patients. From that point of view, total abstention ought to be recommended. If this is not achieved, occasional use of alcohol is probably less harmful than daily drinking for patients with low or moderate alcohol consumption.

Monitoring virological responses to interferon-ribavirin and interferon monotherapy of chronic hepatitis C re-treated due to relapse or non-response.

Adding the nucleoside analog ribavirin (RBV) to interferon (IFN) for treatment of HCV has improved the sustained response rates, but the mechanism by which RBV mediates viral clearance is not fully understood. In this study, a highly sensitive method (Codes Amplicor HCV Monitor) was used to monitor the early (first 12 weeks of therapy) and long-term virological response in 20 patients who were treated first with IFN and later, due to non-sustained response, with IFN-RBV. All 10 IFN relapsers displayed a prompt virological response at week 4 to both IFN and IFN-RBV therapy; nine of them showed a sustained response to IFN-RBV. Out of 10 IFN non-responders, five showed a sustained response to IFN-RBV. Four of these were HCV RNA-negative at week 4 of IFN-RBV therapy and two of them had a transient early virological response (RNA-negative at weeks 4-8) to IFN alone. Overall, of the 14 patients (nine IFN relapsers, five IFN non-responders) with a sustained response to IFN-RBV, 11 and 13 had HCV RNA below 2000 copies/ml at week 4 of IFN and IFN-RBV, respectively, as compared with one and one of six patients without a sustained response to IFN-RBV (p < 0.02). Thus, addition of RBV to IFN increased both viral clearance during the first 12 weeks of therapy and the rate of sustained response. Loss of viremia at week 4 of IFN was associated with a sustained response to IFN-RBV and was seen in 11 of 13 patients (85%) with genotypes 2 or 3, as compared with one of seven patients (14%) with genotype 1 (p = 0.0044).

HCV RNA levels during therapy with amantadine in addition to interferon and ribavirin in chronic hepatitis C patients with previous nonresponse or response/relapse to interferon and ribavirin.

Interferon (IFN) alpha in combination with ribavirin (RIB) is standard therapy for patients with chronic hepatitis C virus (HCV) infection. However, many patients do not respond with sustained HCV clearance to this therapy. At present, no accepted treatment strategy exists for these patients. Recent preliminary data have suggested that amantadine (AMA) is effective against HCV infection. In a pilot study, we treated 13 nonresponders and 10 response/ relapsers to previous IFN/RIB therapy with AMA 200 mg per day in combination with IFN 3 MU thrice weekly, and RIB 1000 mg per day for 24 weeks, with a 24-week follow-up period after end-of-treatment. At the end-of-treatment, 1 previous nonresponder and 5 previous response/relapsers were HCV RNA negative. At the end of follow-up, only 1 previous response/relapser remained HCV RNA negative and had a sustained response. During therapy, serum HCV RNA became undetectable in 4 previous nonresponders, of whom 3 had a breakthrough at week 24. Twenty-one patients continued therapy without dose reductions. One patient discontinued therapy prematurely due to sleeping disturbances, and another patient was withdrawn from therapy due to heavy alcohol intake. We conclude that the addition of AMA to IFN and RIB was well tolerated but had little, if any, impact on HCV RNA eradication in nonresponders or response/relapsers to previous IFN/RIB combination therapy.

Slowed reaction time in HIV-1-infected patients without AIDS.

OBJECTIVES: To investigate if HIV-1-infected patients without acquired immunodeficiency syndrome (AIDS) have cerebral dysfunction as reflected by impaired reaction times compared to patients with chronic hepatitis C. MATERIAL AND METHODS: Forty-one HIV-1-infected patients not fulfilling the AIDS criteria, were tested with three reaction time tests and compared to controls with chronic hepatitis C, matched according to gender and age. RESULTS: HIV-1-infected individuals had, in mean, 5-47 ms longer reaction time than patients with hepatitis C (statistically significant in two of three tests). All but 9 HIV-1-infected individuals had, however, reaction times within the normal range defined by the control group (mean +/- 2 SD). No correlation was found between reaction time and immune status measured as CD4-cell count. CONCLUSION: This study indicates that a subgroup of HIV-1-infected individuals have slower reaction time compatible with cerebral deterioration early in the course of the infection.

Hepatocellular carcinoma in Sweden: its association with viral hepatitis, especially with hepatitis C viral genotypes.

Viral markers of chronic hepatitis were tested for in 95 frozen serum samples from 299 patients from Malmö, Sweden, with hepatocellular carcinoma (HCC), diagnosed between 1977 and 1994. Hepatitis B analysis included anti-HBc, HBsAg and, if anti-HBc positive, HBV DNA. Hepatitis C infection analysis included anti-HCV screening, RIBA, HCV RNA and HCV genotyping. HCV genotyping was also carried out in 9 HCV-viraemic HCC-patients from Gothenburg. HCV genotype distribution in HCC cases was compared with Swedish HCV-infected blood donors. Among the 95 patients from Malmö, 28 (29%) had anti-HBc, but only 5 (5%) were chronic HBV carriers, compared with 16 (17%) with chronic hepatitis C (p = 0.021). HCV-related HCC was more common among immigrants (8/16 vs. 8/79; p < 0.001). Genotyping of 25 HCV-infected cases showed genotype 1a in 6 (24%), genotype 1b in 13 (52%), genotype 2b in 4 (16%), and genotype 3a in 2 (8.0%) patients. Genotype 1b was more common among HCC patients than among blood donors (p < 0.001), but 8 of 13 genotype 1b-infected patients were from countries where genotype 1b is predominant. Among native Swedes there was no difference between the HCV genotypes infecting blood donors and those found in HCC patients.

Chronic hepatitis C in Sweden: genotype distribution over time in different epidemiological settings.

Hepatitis C virus (HCV) strains are divided into 6 genotypes and several subtypes. Recent studies reported a change in the relative frequency of genotypes within certain regions. We studied the HCV genotype in 312 Swedish patients with chronic hepatitis C, using a core region primer-specific PCR, and grouped the patients according to parenteral risk factors. The date of infection could be estimated in 127 cases. Genotypes 1a (35%) and 3 (31%) were the most common genotypes, followed by genotype 2 (17%), while only 6% had genotype 1b. Genotype 3 was relatively more frequent among subjects infected sexually or by intravenous drug use. The genotype distribution was different from that in studies from other parts of the world, with a lower frequency of genotype 1 (especially 1b) and a higher frequency of genotype 3. The frequency of genotype 1b has decreased and genotype 3 increased over time. The reasons for a different distribution of genotypes in Sweden, compared with other countries, might be a relatively recent introduction of HCV into the population, or a different pattern of transmission.

Interobserver study of liver histopathology using the Ishak score in patients with chronic hepatitis C virus infection.

AIMS/BACKGROUND: Assessing the histopathological degree of liver damage is essential to the routine care of patients with chronic hepatitis C virus (HCV) infection. Several scoring systems have been proposed in attempts to standardize the histological assessment. One scoring system has been proposed by Ishak et al. Although widely endorsed, its interobserver reliability has not been evaluated. METHODS: 95 liver biopsies from patients with chronic HCV infection were scored by three independent observers. Interface hepatitis, confluent necrosis, focal necrosis, portal inflammation, and fibrosis were assessed. RESULTS: Confluent necrosis, which is more common in acute hepatitis, was not seen in any biopsy. For each of the remaining variables of inflammation (periportal hepatitis, focal necrosis, and portal inflammation) we found agreement in 95-96% for all three observers. Kappa scores ranged from 0.11 to 0.41 and weighted kappa scores from 0.18 to 0.53. For staging we noted 84% agreement, kappa scores of 0.26-0.47, and weighted kappa scores of 0.57-0.69. CONCLUSION: The Ishak system is associated with good interobserver reliability if a deviance of one categorical level in each variable of the system is accepted as agreement. Compared to the Knodell system it provides more detailed information but is less reliable regarding fibrosis.

Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon.

BACKGROUND/AIMS: This study aimed to determine the long-term outcome of hepatitis C virus (HCV)-infected patients who respond to interferon treatment with clearance of serum HCV RNA. METHODS: We performed a long-term biochemical, virological, and histological follow-up of all sustained virological responders, defined as those who became HCV RNA negative at follow-up 6 months after the end of treatment, from 3 controlled interferon trials performed in Sweden between 1988 and 1994. RESULTS: At biochemical and virological long-term follow-up performed in 26 sustained virological responders 3.5-8.8 years (mean +/- SD, 5.4+/-1.6 years) after the end of IFN therapy, 22 patients (85%) had normal serum ALT levels, and 24 patients (92%) were HCV RNA negative in serum. Liver biopsies performed in 23 patients 2.1-8.7 years (mean +/- SD, 5.0+/-1.8 years) after end of treatment showed no or minimal inflammation, whereas mild and probably irreversible fibrosis was seen in a few patients. CONCLUSION: In this well-defined material of sustained responders to IFN therapy, the long-term prognosis was excellent. Nearly all had a durable response, not only biochemically and virologically, but more importantly also histologically with normalisation or near normalisation of previous histological lesions.

[Hepatitis G virus exists--but does hepatitis G?]. / Hepatit G-virus finns--men finns hepatit G?

Hepatitis G virus, or GB virus type C, is a recently discovered RNA virus, remotely related to hepatitis C virus. The infection is frequently found, and seems to be blood-borne, occurring among intravenous drug abusers and transmitted from mother to child. Although long-term viraemia is common, in most cases the infection resolves spontaneously. Whether the viral infection causes liver disease or has other manifestations remains unknown.

Sexual transmission of hepatitis C virus.

Sexual transmission of hepatitis C virus (HCV) occurs; however, to what extent is still unclear. In this presentation relevant data from the literature concerning the following key issues will be presented: presence of HCV in the seminal fluid and vaginal secretions; presence of HCV infection in sexually promiscuous individuals; presence of HCV infection among sexual partners to HCV-infected individuals; and molecular biology evidence of sexual transmission. An anti-HCV prevalence of 2-12% is seen in sexually promiscuous individuals, which is higher than that usually seen among blood donors. In case-control studies, HCV infection is associated with sexual promiscuity and sex with a partner who has a past history of hepatitis. In most studies, HCV infection is common among sexual partners of HCV-infected subjects. Genotyping and genome sequencing provide further evidence for intraspousal transmission of HCV Despite these findings, stable sexual partners of hemophiliacs or recipients of HCV-contaminated immunoglobulin preparations rarely become infected. These discrepancies are not fully understood. Other sexual behaviours or confounding non-sexual transmission routes could play a part.

Perinatal transmission of hepatitis G virus (GB virus type C) and hepatitis C virus infections--a comparison.

Hepatitis G virus (HGV) infection is more common than hepatitis C virus (HCV) infection and is frequently found in healthy individuals. Although parenteral spread of HGV is well recognized, other routes of transmission probably occur as well. In a prospective study of mother-to-infant transmission of hepatitis viruses, 69 pregnant women with antibodies to HCV and their 81 newborn children were included. Serum levels of HCV RNA and HGV RNA were detected by polymerase chain reaction (PCR) assays, and antibodies to HCV and HGV envelope protein E2 were detected by enzyme-linked immunosorbent assay. Fifty-nine of the mothers had HCV viremia, whereas 16 had HGV viremia. HCV transmission from viremic mothers occurred in 2.8%-4.2% of the cases, whereas HGV transmission from viremic mothers occurred in 75.0%-80.0% of the cases (P < .001). Sequencing of the PCR products of HGV from the mother-infant serum pairs showed minor differences in most cases but sequence homology in each pair. Although the rate of perinatal HGV transmission highly exceeded that of perinatal HCV transmission, HGV did not seem to induce hepatitis in the children.

HCV-RNA levels increase during pregnancy in women with chronic hepatitis C.

Alanine aminotransferase (ALT) levels decline during pregnancy in women chronically infected with hepatitis C virus (HCV). In order to understand further the underlying mechanisms, we prospectively followed 10 chronically infected women before, during and after pregnancy. ALT levels were analysed together with quantification of serum HCV-RNA using the branched DNA technology. As anticipated, the ALT levels significantly declined late in pregnancy and increased again after delivery. HCV-RNA levels, conversely, significantly increased late in pregnancy and returned to baseline levels 1 y after delivery. These findings suggest the importance of immune mediated mechanisms in controlling the viral replication and contributing to the liver injury in chronic hepatitis C.

Histamine and the response to IFN-alpha in chronic hepatitis C.

Whole blood concentrations of histamine were examined in 20 patients with chronic hepatitis C after longterm treatment with interferon-alpha (IFN-alpha). In 13 of these patients, a transient (n = 5) or sustained (n = 8) normalization of liver enzymes and elimination of viral RNA were noted at the end of therapy. Seven patients did not respond to IFN-alpha. Nonresponding patients had significantly lower histamine levels in blood than transient (p = 0.0005) or sustained (p = 0.04) responders. Histamine levels were not different in patients with a sustained vs. a transient IFN response. Confounding factors, such as ongoing viral replication or liver cirrhosis, did not account for the differences in histamine levels. Our data suggest that hypohistaminism in peripheral blood may determine a poor response to IFN-alpha in chronic hepatitis C.

The importance of cofactors in the histologic progression of minimal and mild chronic hepatitis C.

A follow-up liver biopsy was done 9-16 years (mean 12 years) after initial biopsy in 20 untreated Swedish patients infected with hepatitis C (8 men, 12 women; mean age 30 years at initial biopsy) in whom first biopsy had been classified as chronic persistent hepatitis. A significant progression of liver damage was found when using Histology Activity Index (HAI) scoring according to Knodell (p=0.006 for total HAI score; p=0.03 for grading, i.e., sum of HAI components 1, 2, and 3; p=0.01 for staging, i.e., HAI component 4, fibrosis). Fourteen of 20 (70%) patients had increased while 6 had decreased or unchanged HAI scores on follow-up biopsy. Occasional heavy alcohol drinkers (n=6) had an increased follow-up HAI score as compared with nondrinkers (p<0.05). Eight of 14 who deteriorated on follow-up versus 0 of 6 with improved or unchanged liver histology were anti-HBc positive (p=0.04). There was no significant correlation between HCV genotype and prognosis; however, the only two patients with liver cirrhosis on follow-up had genotype 1b. In conclusion, most patients with minimal or mild chronic hepatitis C in the present study had histologic progression on the latest biopsy. Cofactors such as alcohol abuse and exposure to hepatitis B may have a greater influence than HCV alone in determining the rate of deterioration of liver disease.